Hallucinogens such as LSD and DOM increase extracellular glutamate in the prefrontal cortex of rats, as shown by in vivo microdialysis. LSD (0.1 mg/kg) caused a time-dependent rise in glutamate that was blocked by a 5-HT(2A) antagonist. DOM (0.6 mg/kg) raised glutamate to 206% above controls. Direct application of LSD to the prefrontal cortex via reverse dialysis also rapidly increased glutamate, which remained elevated after infusion stopped. These findings suggest that enhanced glutamate release is a shared mechanism in the action of hallucinogens.
The hallucinogen 2C-T-7 produces head twitch responses in mice and serves as a discriminative stimulus in rats, effects that are blocked by a selective 5-HT2A antagonist. In drug discrimination tests, 2C-T-7 partially generalized (75%) to the LSD cue in rats and acted as a discriminative stimulus itself, with those interoceptive effects also attenuated by the 5-HT2A antagonist. Binding studies show 2C-T-7 has nanomolar affinity for 5-HT2A and 5-HT2C receptors and lower affinity for 5-HT1A receptors. The antagonism of its behavioral effects strongly suggests the 5-HT2A receptor is an important site of action for this compound.
In rats trained to distinguish LSD from saline, several N-substituted tryptamines produced intermediate levels of LSD-like responding: MDMT (76.4%), DMT (77.9%), and DET (48.7%). 6-F-DET elicited 41.3% LSD-appropriate responding at 6.0 mg/kg, but only 4 of 8 subjects completed the session, precluding statistical analysis. Bufotenine (25.8%) failed to substitute. None of the tryptamines substituted completely for LSD, though the pattern aligns with their known human hallucinogenic activity. Among beta-carbolines tested, only harmane showed intermediate substitution (49.5%); others, including harmaline and THBC, showed no significant generalization. The tryptamines overall showed greater similarity to the LSD stimulus than the beta-carbolines did.